The aims of this project are to better understand the mechanisms and modulation of pain associated with tissue in the oral cavity and adjacent structures (i.e., the teeth, gums, cheek, jaw muscles, and temporomandibular joint). The mechanisms of pain, and pain modulation from the oral cavity remain largely unknown. Therefore, the long term goal of this project is to improve management of dental-related pain. Tissue damage will be induced in the oral the cavity or surrounding structures. This will be done by removing enamel and dentin from the teeth, or by using one of a variety of agents to induce inflammation in the gums, bone/joints, masseter muscle, or check mucosa. Following tissue insult electrophysiology and behavioral studies will be performed. Stimuli to be used will include electrical, thermal, chemical, and mechanism stimulation of the teeth, gums, gingiva, masseter, and temporomandibular joint. Neuronal responses to these stimuli will be modulated by intracerebral electrical stimulation or drugs. In conscious rats behavioral responses to various mechanical and chemical stimuli will be monitored in behavioral assays as well as a passive avoidance paradigm. In no cases will the stimulus be uncontrolled or of duration that produces tissue damage. These will be the definitive experiments used in determining whether the described chemical and mechanical stimuli are involved in the etiology of pain arising from the oral cavity. This project proposes to use a multi-disciplinary approach incorporating a variety of anatomical, pharmacological, neurochemical and behavioral techniques to address three specific aims: (1) to examine and compare the mechanisms responsible for the expression of the behavioral symptoms produced by the various tissue insults; (2) to characterize the necessary stimulus, either mechanical or chemical, in each tissue insult model, to produce behavioral evidence of pain; (3) to examine the role of neurotransmitters and neuromodulators in the central and peripheral nervous systems in the development and /or maintenance of the behavioral symptoms produced in oral cavity pain models. The research represents a systematic examination of the pathology neurochemistry, and anatomy underlying the causative mechanisms of oral pain and should yield valuable information concerning the treatment and management of oral pain. KEYWORDS: Pharmacological, Neurochemical, Oral Pain